Central nervous system (CNS) physiology requires special chemical, metabolic and cellular privileges for normal function, and blood brain barrier (BBB) structures are the anatomic and physiologic constructs that arbitrate communication between the brain and body. A functionally integrated set of chemical protection properties established by the genes expressed in BBB cell layers combine to control small molecule access to the CNS. A better description of the fundamental metabolic control processes at the BBB is a key roadblock in understanding CNS physiology under hypoxic, metabolic and chemical stress conditions. Furthermore the vast majority of drugs do not pass into the brain because of the same highly integrated chemical protection mechanisms of the BBB. In order to better understand metabolic control of the brain space, the physical means and organizational logic behind the many independent chemical exclusion operations performed by the BBB must be determined. The Drosophila BBB, a glially derived barrier, possesses similar physiologic properties, highly homologous genetic components, and similar cellular anatomy to the vertebrate BBB. Furthermore Drosophila genetic tools allow for systematic and rapid interrogation of multiple BBB cell layers in whole animals and under normal physiological conditions thus localizing specific chemical isolation and communication mechanisms with great precision. To decipher essential BBB components and specific control elements at multiple levels the BBB transcriptome is an invaluable tool. In preliminary studies a precise transcriptional profile of the fly BBB was produced and bioinformatically compared to similar vertebrate BBB data sets that include the vascular endothelium (VE) and associated astrocytic glia (AG). The initial analysis shows remarkable functional similarities between Drosophila and vertebrate BBBs as hundreds of highly homologous genes are greatly enriched in both data sets including many metabolic transporters. These data suggest that a set of highly evolutionary conserved physiologies is present at the cellular layers of the BBB. This proposal uses the power of the Drosophila BBB system and comparative genomics to discover cell autonomous chemical protection mechanisms, intercellular compensations, and systemic signals that regulate BBB function. It weaves together genetic, genomic, and physiologic methods to deepen our understanding of the complex integration of sophisticated cellular anatomy and highly polarized chemical protection physiology. With these insights it will be possible to decipher the rules of chemical isolation and assign best use target pathways for getting drugs into the brain. Ultimately, these insights will deliver novel testable hypothesis to vertebrate systems for future studies in genetic or chemical modulating of BBB function.